This K08 proposal describes a four-year research and training plan that will facilitate the transition of Dr. Brian Kalish to an independent academic researcher in the field of neuronal chromatin biology. Dr. Kalish has a strong background in basic research and recently completed post-graduate training in neonatal-perinatal medicine. Dr. Kalish is interested in the molecular mechanisms underlying neurodevelopmental disorders, and in using insights from these disorders to better understand normal brain development. To this end, Dr. Kalish has identified a novel activity-dependent post-translational switch on a histone lysine methyltransferase, SETD2, that regulates its interactome and function. The overarching aim of this proposal is to obtain a more comprehensive understanding of the activity-dependent regulation of the epigenome by elucidating the molecular mechanisms underlying the function of SETD2 in the brain. SETD2 is strongly implicated in intellectual disability and autism, and therefore represents an ideal candidate through which to link pathophysiological changes characteristic of neurodevelopmental disorders to defined alterations in gene expression and chromatin structure. The candidate proposes three specific aims: 1. Characterize the temporal and stimulus-specific dynamics of neuronal activity-dependent SETD2 phosphorylation; 2. Investigate how activity-dependent phosphorylation of SETD2 disrupts interaction with a chromatin-remodeling complex; and 3. Study the role of SETD2 phosphorylation in activity-dependent transcription and alternative splicing using a novel SETD2 phospho-mutant mouse. This research has significance, as knowledge gained from this study will impact our understanding of epigenetic regulation in the brain, as well as our knowledge of neurodevelopmental disorders. Dr. Kalish will receive mentorship from his scholarship oversight committee composed of distinguished scientists with expertise related to key areas of this proposal. The training opportunities and resources at Harvard Medical School are an ideal environment for the candidate?s career development program. The candidate?s mentor, Dr. Michael Greenberg, is a NIH funded neurobiologist with a track record of successful mentorship. A detailed career development and training plan is presented that includes mentored research, didactic coursework, self-directed readings, seminars, and presentations at scientific meetings. The candidate details a timeline for completion of the research aims, preparation of manuscripts, and a future R01 application. The expertise and knowledge gained from this K08 will enable Dr. Kalish to obtain R01 funding to launch an independent research career focused on the regulation of the epigenome in brain development and disorders.